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Hypertrophic cardiomyopathy (HCM) may lead to cardiac dysfunction and sudden death. This study was designed to develop a HCM signature applying bioinformatics and machine learning methods. Data of HCM and normal tissues were obtained from public databases to screen differentially expressed genes (DEGs) using the R software limma package. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were performed for enrichment analysis of HCM-associated DEGs. Hub genes for HCM were determined using weighted gene co-expression network analysis (WGCNA) together with two machine learning algorithms (SVM-RFE and LASSO). Finally, we introduced a zebrafish model to simulate changes in the hub genes in the HCM and to observe their effects on cardiac disease development. The mRNA expression data from a total of 106 HCM tissues and 39 normal samples were collected and we screened 157 DEGs. Enrichment analysis showed that immune pathways played an important role in the pathogenesis of HCM. Three hub genes (FCN3, MYH6 and RASD1) were identified using WGCNA, SVM-RFE, and LASSO analysis. In a zebrafish model, knockdown of MYH6 and RASD1 resulted in cardiac malformations with reduced ventricular capacity and heart rate, which validated the clinical significance of these genes in the diagnosis of HCM. Based on machine learning algorithms, our study created a signature with potential impact on cardiac function and cardiac quality index for HCM. The current findings had important implications for the early diagnosis and treatment of HCM.
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Cardiomiopatía Hipertrófica , Perfilación de la Expresión Génica , Aprendizaje Automático , ARN Mensajero , Pez Cebra , Cardiomiopatía Hipertrófica/genética , Animales , Pez Cebra/genética , Humanos , ARN Mensajero/genética , ARN Mensajero/metabolismo , Redes Reguladoras de Genes , Biología Computacional/métodos , Transcriptoma/genética , Modelos Animales de EnfermedadRESUMEN
Infection with Glaesserella parasuis, the primary pathogen behind Glässer's disease, is often associated with diverse clinical symptoms, including serofibrinous polyserositis, arthritis, and meningitis. Autophagy plays a dual role in bacterial infections, exerting either antagonistic or synergistic effects depending on the nature of the pathogen. Our previous studies have demonstrated that autophagy serves as a defense mechanism, combating inflammation and invasion caused by infection of highly virulent G. parasuis. However, the precise mechanisms remain to be elucidated. Pathogens exhibit distinct interactions with inflammasomes and autophagy processes. Herein, we explored the effect of autophagy on inflammasomes during G. parasuis infection. We found that G. parasuis infection triggers NLRP3-dependent pro-CASP-1-IL-18/IL-1ß processing and maturation pathway, resulting in increased release of IL-1ß and IL-18. Inhibition of autophagy enhances NLRP3 inflammasome activity, whereas stimulation of autophagy restricts it during G. parasuis infection. Furthermore, assembled NLRP3 inflammasomes undergo ubiquitination and recruit the autophagic adaptor, p62, facilitating their sequestration into autophagosomes during G. parasuis infection. These results suggest that the induction of autophagy mitigates inflammation by eliminating overactive NLRP3 inflammasomes during G. parasuis infection. Our research uncovers a mechanism whereby G. parasuis infection initiates inflammatory responses by promoting the assembly of the NLRP3 inflammasomes and activating NLRP3-CASP-1, both of which processes are downregulated by autophagy. This suggests that pharmacological manipulation of autophagy could be a promising approach to modulate G. parasuis-induced inflammatory responses.
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Autofagia , Caspasa 1 , Infecciones por Haemophilus , Haemophilus parasuis , Inflamasomas , Proteína con Dominio Pirina 3 de la Familia NLR , Animales , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Inflamasomas/inmunología , Inflamasomas/metabolismo , Haemophilus parasuis/inmunología , Haemophilus parasuis/patogenicidad , Haemophilus parasuis/genética , Caspasa 1/metabolismo , Caspasa 1/genética , Infecciones por Haemophilus/veterinaria , Infecciones por Haemophilus/inmunología , Infecciones por Haemophilus/microbiología , Porcinos , Interleucina-18/metabolismo , Interleucina-18/genética , Interleucina-1beta/metabolismo , Interleucina-1beta/genética , Enfermedades de los Porcinos/microbiología , Enfermedades de los Porcinos/inmunología , RatonesRESUMEN
Background: The incidence of prostate cancer (PC) has increased in recent years. Erectile dysfunction (ED) after prostate cancer treatment has aroused extensive attention. Bibliometric analysis was designed to investigate a systematic understanding of developments between PC and ED during the past 20 years. Methods: Literatures on PC and ED were retrieved from the Web of Science Core Collection database (WoSCC). By using the VOS viewer and CiteSpace software to analysis the metrics of bibliometric literature, such as number of articles, journals, countries, institutions, authors, keywords and associated information. The number of publications per year was statistically analysed and plotted thorough Microsoft Office. In addition, Pajek software was used to adjust the visual map. Results: A total of 2332 screened articles were included in the analysis. The Journal of Sexual Medicine, ranking first among the analysed journals, published 235 articles. The United States and Canada were leaders in PC and ED research. There is a need to strengthen inter-agency cooperation in this area of research on a global scale. Mulhall JP, as the most prolific author in this area of research, published 80 articles. And Rosen RC was the author with the most co-citated (693 co-citated). The main research focus on the prevention, treatment and management of ED after PC treatment in this field through the keyword analysis. Conclusions: Research on PC and ED is expected to expand further worldwide. We found ED, as new sustainable treatment modalities, scientific postoperative management and psychological interventions for patients, may become the research hotspots and should be closely concerned in this study.
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BACKGROUND: Gastropods of the genus Biomphalaria (Family Planorbidae) are exploited as vectors by Schistosoma mansoni, the most common causative agent of human intestinal schistosomiasis. Using improved genomic resources, overviews of how Biomphalaria responds to S. mansoni and other metazoan parasites can provide unique insights into the reproductive, immune, and other systems of invertebrate hosts, and their responses to parasite challenges. RESULTS: Using Illumina-based RNA-Seq, we compared the responses of iM line B. glabrata at 2, 8, and 40 days post-infection (dpi) to single infections with S. mansoni, Echinostoma paraensei (both digenetic trematodes) or Daubaylia potomaca (a nematode parasite of planorbid snails). Responses were compared to unexposed time-matched control snails. We observed: (1) each parasite provoked a distinctive response with a predominance of down-regulated snail genes at all time points following exposure to either trematode, and of up-regulated genes at 8 and especially 40dpi following nematode exposure; (2) At 2 and 8dpi with either trematode, several snail genes associated with gametogenesis (particularly spermatogenesis) were down-regulated. Regarding the phenomenon of trematode-mediated parasitic castration in molluscs, we define for the first time a complement of host genes that are targeted, as early as 2dpi when trematode larvae are still small; (3) Differential gene expression of snails with trematode infection at 40dpi, when snails were shedding cercariae, was unexpectedly modest and revealed down-regulation of genes involved in the production of egg mass proteins and peptide processing; and (4) surprisingly, D. potomaca provoked up-regulation at 40dpi of many of the reproduction-related snail genes noted to be down-regulated at 2 and 8dpi following trematode infection. Happening at a time when B. glabrata began to succumb to D. potomaca, we hypothesize this response represents an unexpected form of fecundity compensation. We also document expression patterns for other Biomphalaria gene families, including fibrinogen domain-containing proteins (FReDs), C-type lectins, G-protein coupled receptors, biomphalysins, and protease and protease inhibitors. CONCLUSIONS: Our study is relevant in identifying several genes involved in reproduction that are targeted by parasites in the vector snail B. glabrata and that might be amenable to manipulation to minimize their ability to serve as vectors of schistosomes.
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Biomphalaria , Schistosoma mansoni , Transcriptoma , Animales , Biomphalaria/parasitología , Biomphalaria/genética , Schistosoma mansoni/genética , Schistosoma mansoni/fisiología , Interacciones Huésped-Parásitos/genética , Trematodos/fisiología , Trematodos/genética , Vectores de Enfermedades , Perfilación de la Expresión GénicaRESUMEN
Background: Glioma pathogenesis related-2 (GLIPR2), an emerging Golgi membrane protein implicated in autophagy, has received limited attention in current scholarly discourse. Methods: Leveraging extensive datasets, including The Cancer Genome Atlas (TCGA), Genotype Tissue Expression (GTEx), Human Protein Atlas (HPA), and Clinical Proteomic Tumor Analysis Consortium (CPTAC), we conducted a comprehensive investigation into GLIPR2 expression across diverse human malignancies. Utilizing UALCAN, OncoDB, MEXPRESS and cBioPortal databases, we scrutinized GLIPR2 mutation patterns and methylation landscapes. The integration of bulk and single-cell RNA sequencing facilitated elucidation of relationships among cellular heterogeneity, immune infiltration, and GLIPR2 levels in pan-cancer. Employing ROC and KM analyses, we unveiled the diagnostic and prognostic potential of GLIPR2 across diverse cancers. Immunohistochemistry provided insights into GLIPR2 expression patterns in a multicenter cohort spanning various cancer types. In vitro functional experiments, including transwell assays, wound healing analyses, and drug sensitivity testing, were employed to delineate the tumor suppressive role of GLIPR2. Results: GLIPR2 expression was significantly reduced in neoplastic tissues compared to its prevalence in healthy tissues. Copy number variations (CNV) and alterations in methylation patterns exhibited discernible correlations with GLIPR2 expression within tumor tissues. Moreover, GLIPR2 demonstrated diagnostic and prognostic implications, showing pronounced associations with the expression profiles of numerous immune checkpoint genes and the relative abundance of immune cells in the neoplastic microenvironment. This multifaceted influence was evident across various cancer types, with lung adenocarcinoma (LUAD) being particularly prominent. Notably, patients with LUAD exhibited a significant decrease in GLIPR2 expression within practical clinical settings. Elevated GLIPR2 expression correlated with improved prognostic outcomes specifically in LUAD. Following radiotherapy, LUAD cases displayed an increased presence of GLIPR2+ infiltrating cellular constituents, indicating a notable correlation with heightened sensitivity to radiation-induced therapeutic modalities. A battery of experiments validated the functional role of GLIPR2 in suppressing the malignant phenotype and enhancing treatment sensitivity. Conclusion: In pan-cancer, particularly in LUAD, GLIPR2 emerges as a promising novel biomarker and tumor suppressor. Its involvement in immune cell infiltration suggests potential as an immunotherapeutic target.
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Adenocarcinoma del Pulmón , Glioma , Neoplasias Pulmonares , Humanos , Variaciones en el Número de Copia de ADN , Proteómica , Biomarcadores , Microambiente TumoralRESUMEN
Schistosomiasis is one of the world's most devastating parasitic diseases, afflicting 251 million people globally. The Neotropical snail Biomphalaria glabrata is an important intermediate host of the human blood fluke Schistosoma mansoni and a predominant model for schistosomiasis research. To fully exploit this model snail for biomedical research, here we report a haplotype-like, chromosome-level assembled and annotated genome of the homozygous iM line of B. glabrata that we developed at the University of New Mexico. Using multiple sequencing platforms, including Illumina, PacBio, and Omni-C sequencing, 18 sequence contact matrices representing 18 haploid chromosomes (2n = 36) were generated (337x genome coverage), and 96.5% of the scaffold sequences were anchored to the 18 chromosomes. Protein-coding genes (n = 34,559), non-coding RNAs (n = 2,406), and repetitive elements (42.52% of the genome) were predicted for the whole genome, and detailed annotations for individual chromosomes were also provided. Using this genomic resource, we have investigated the genomic structure and organization of the Toll-like receptor (TLR) and fibrinogen-domain containing protein (FReD) genes, the two important immune-related gene families. Notably, TLR-like genes are scattered on 13 chromosomes. In contrast, almost all (39 of 40) fibrinogen-related genes (FREPs) (immunoglobulin superfamily (IgSF) + fibrinogen (FBG)) are clustered within a 5-million nucleotide region on chromosome 13, yielding insight into mechanisms involved in the diversification of FREPs. This is the first genome of schistosomiasis vector snails that has been assembled at the chromosome level, annotated, and analyzed. It serves as a valuable resource for a deeper understanding of the biology of vector snails, especially Biomphalaria snails.
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Biomphalaria , Hemostáticos , Esquistosomiasis , Humanos , Animales , Biomphalaria/genética , Haplotipos , Fibrinógeno , Cromosomas/genéticaRESUMEN
Implant-associated infections (IAIs) pose a significant threat to orthopedic surgeries. Bacteria colonizing the surface of implants disrupt bone formation-related cells and interfere with the osteoimmune system, resulting in an impaired immune microenvironment and osteogenesis disorders. Inspired by nature, a zeolitic imidazolate framework (ZIF)-sealed smart drug delivery system on Ti substrates (ZSTG) was developed for the "natural-artificial dual-enzyme intervention (NADEI)" strategy to address these challenges. The subtle sealing design of ZIF-8 on the TiO2 nanotubes ensured glucose oxidase (GOx) activity and prevented its premature leakage. In the acidic infection microenvironment, the degradation of ZIF-8 triggered the rapid release of GOx, which converted glucose into H2O2 for disinfection. The Zn2+ released from degraded ZIF-8, as a DNase mimic, can hydrolyze extracellular DNA, which further enhances H2O2-induced disinfection and prevents biofilm formation. Importantly, Zn2+-mediated M2 macrophage polarization significantly improved the impaired osteoimmune microenvironment, accelerating bone repair. Transcriptomics revealed that ZSTG effectively suppressed the inflammatory cascade induced by lipopolysaccharide while promoting cell proliferation, homeostasis maintenance, and bone repair. In vitro and in vivo results confirmed the superior anti-infective, osteoimmunomodulatory, and osteointegrative capacities of the ZSTG-mediated NADEI strategy. Overall, this smart bionic platform has significant potential for future clinical applications to treat IAIs.
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Antiinfecciosos , Zeolitas , Oseointegración , Peróxido de Hidrógeno/farmacología , Macrófagos , Antiinfecciosos/farmacología , OsteogénesisRESUMEN
Schistosomiasis, urogenital and intestinal, afflicts 251 million people worldwide with approximately two-thirds of the patients suffering from the urogenital form of the disease. Freshwater snails of the genus Bulinus (Gastropoda: Planorbidae) serve as obligate intermediate hosts for Schistosoma haematobium, the etiologic agent of human urogenital schistosomiasis. These snails also act as vectors for the transmission of schistosomiasis in livestock and wildlife. Despite their crucial role in human and veterinary medicine, our basic understanding at the molecular level of the entire Bulinus genus, which comprises 37 recognized species, is very limited. In this study, we employed Illumina-based RNA sequencing (RNAseq) to profile the genome-wide transcriptome of Bulinus globosus, one of the most important intermediate hosts for S. haematobium in Africa. A total of 179,221 transcripts (N50 = 1,235) were assembled and the benchmarking universal single-copy orthologs (BUSCO) was estimated to be 97.7%. The analysis revealed a substantial number of transcripts encoding evolutionarily conserved immune-related proteins, particularly C-type lectin (CLECT) domain-containing proteins (n = 316), Toll/Interleukin 1-receptor (TIR)-containing proteins (n = 75), and fibrinogen related domain-containing molecules (FReD) (n = 165). Notably, none of the FReDs are fibrinogen-related proteins (FREPs) (immunoglobulin superfamily (IgSF) + fibrinogen (FBG)). This RNAseq-based transcriptional profile provides new insights into immune capabilities of Bulinus snails, helps provide a framework to explain the complex patterns of compatibility between snails and schistosomes, and improves our overall understanding of comparative immunology.
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Bulinus , Esquistosomiasis Urinaria , Humanos , Animales , Bulinus/genética , Schistosoma haematobium/genética , Agua Dulce , FibrinógenoRESUMEN
Mitotic catastrophe (MC) is a novel form of cell death that plays an important role in the treatment and drug resistance of colon adenocarcinoma (COAD). However, MC related genes in COAD treatment and prognosis evaluation are rarely studied. In this study, the transcriptome data, somatic mutation and copy number variation data were obtained from The Cancer Genome Atlas (TCGA) database. The mitotic catastrophe related genes (MCRGs) were obtained from GENCARDS website. Differential gene analysis was conducted with LIMMA package. Univariate Cox regression analysis was used to identify prognostic related genes. Mutation analysis was performed and displayed by maftools package. RCircos package was used for localizing the position of genes on chromosomes. "Glmnet" R package was applied for constructing a risk model via the LASSO regression method. Consensus clustering analyses was implemented for clustering different subtypes. Functional enrichment analysis through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) methods, immune infiltration analysis via single sample gene set enrichment analysis (ssGSEA), tumor mutation burden and drug sensitivity analysis by pRRophetic R package were also carried out for risk model or molecular subtype's assessment. Additionally, the connections between the expression of hub genes and overall survival (OS) were obtained from online Human Protein Atlas (HPA) website. Real-Time Quantitative Polymerase Chain Reaction (RTqPCR) further validated the expression of hub genes. A total of 207 differentially expressed MCRGs were selected in the TCGA cohort, 23 of which were significantly associated with OS in COAD patients. Subsequently, we constructed risk score prognostic models with 5 hub MCRGs, including SYCE2, SERPINE1, TRIP6, LIMK1, and EEPD1. The high-risk patients suffered from poorer prognosis. Furthermore, we developed a nomogram that gathered age, sex, staging, and risk score to accurately forecast the clinical survival outcomes in 1, 3, and 5 years. The results of functional enrichment suggested a significant correlation between MCRGs characteristics and cancer progression, with important implications for the immune microenvironment. Moreover, patients who displayed high TMB and high risk score showed worse prognosis, and risk characteristics were associated with different chemotherapeutic agents. Finally, RTqPCR verified the increased expression of the five MCRGs in clinical samples. The five MCRGs in the prognostic signature were associated with prognosis, and could be treated as reliable prognostic biomarkers and therapeutic targets for COAD patients with distinct clinicopathological characteristics, thereby providing a foundation for the precise application of pertinent drugs in COAD patients.
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Adenocarcinoma , Neoplasias del Colon , Humanos , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/genética , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/genética , Variaciones en el Número de Copia de ADN/genética , Pronóstico , Muerte Celular , Microambiente Tumoral , Quinasas Lim , Factores de Transcripción , Proteínas Adaptadoras Transductoras de Señales , Proteínas con Dominio LIMRESUMEN
Vitellogenesis is the most important process in animal reproduction, in which yolk proteins play a vital role. Among multiple yolk protein precursors, vitellogenin (Vtg) is a well-known major yolk protein (MYP) in most oviparous animals. However, the nature of MYP in the freshwater gastropod snail Biomphalaria glabrata remains elusive. In the current study, we applied bioinformatics, tissue-specific transcriptomics, ovotestis-targeted proteomics, and phylogenetics to investigate the large lipid transfer protein (LLTP) superfamily and ferritin-like family in B. glabrata. Four members of LLTP superfamily (BgVtg1, BgVtg2, BgApo1, and BgApo2), one yolk ferritin (Bg yolk ferritin), and four soma ferritins (Bg ferritin 1, 2, 3, and 4) were identified in B. glabrata genome. The proteomic analysis demonstrated that, among the putative yolk proteins, BgVtg1 was the yolk protein appearing in the highest amount in the ovotestis, followed by Bg yolk ferritin. RNAseq profile showed that the leading synthesis sites of BgVtg1 and Bg yolk ferritin are in the ovotestis (presumably follicle cells) and digestive gland, respectively. Phylogenetic analysis indicated that BgVtg1 is well clustered with Vtgs of other vertebrates and invertebrates. We conclude that, vitellogenin (BgVtg1), not yolk ferritin (Bg yolk ferritin), is the major yolk protein precursor in the schistosomiasis vector snail B. glabrata.
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Biomphalaria , Esquistosomiasis , Animales , Biomphalaria/genética , Vitelogeninas/genética , Vitelogeninas/metabolismo , Multiómica , Filogenia , Proteómica , Proteínas del Huevo/metabolismo , Ferritinas/genética , Schistosoma mansoni/metabolismoRESUMEN
The recently discovered APRO (anti-proliferative protein) family encodes a group of trans-membrane glycoproteins and includes 6 members: TOB1, TOB2, BTG1, BTG2, BTG3 and BTG4. The APRO family is reportedly associated with the initiation and progression of cancers. This study aims to undertake a comprehensive investigation of the APRO family of proteins as a prognostic biomarker in various human tumors. We performed a pan-cancer analysis of the APRO family based on The Cancer Genome Atlas (TCGA). With the bioinformatics methods, we explored the prognostic value of the APRO family and the correlation between APRO family expression and tumor mutation burden (TMB), microsatellite instability (MSI), drug sensitivity, and immunotherapy in numerous cancers. Our results show that the APRO family was primarily down-regulated in cancer samples. The expression of APRO family members was linked with patient prognosis. In addition, APRO family genes showed significant association with immune infiltrate subtypes, tumor microenvironment, and tumor cell stemness. Finally, our study also demonstrated the relationship between APRO family genes and drug sensitivity. This study provides comprehensive information to understand the APRO family's role as an oncogene and predictor of survival in some tumor types.
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Proteínas Inmediatas-Precoces , Neoplasias , Humanos , Oncogenes , Inmunoterapia , Cognición , Biología Computacional , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Microambiente Tumoral/genética , Proteínas Supresoras de Tumor/genéticaRESUMEN
Objective: Pelvic inflammatory disease (PID) is a prevalent gynecological disorder. Dietary trace minerals play an important role in combating many chronic diseases including PID. However, it is unknown whether dietary trace minerals and PID are related. This study aimed to examine the relationship between dietary trace minerals (copper, iron, selenium, and zinc) and PID. Methods: Data of women participants from the National Health and Nutrition Examination Survey (NHANES) 2015-2018 were enrolled in this cross-sectional investigation. Univariate and multivariate linear regression analyses of the relationship between dietary trace minerals and PID were performed, and restricted cubic spline (RCS) analyses were applied to visualize those relationships. Results: In total, 2,694 women between the ages of 20 and 59 years participated in the two NHANES cycles. In the univariate analyses, a significant negative relationship was identified between PID and dietary copper intake [odds ratio (OR) = 0.40, 95% confidence interval (CI): 0.24-0.67, p < 0.01] but not with iron (OR = 0.96, 95% CI: 0.90-1.03, p = 0.25), selenium (OR = 1.0, 95% CI: 0.99-1.0, p = 0.23), and zinc (OR = 0.94, 95% CI: 0.86-1.03, p = 0.17) intake. Following the adjustment for age and race (model 1), a robust correlation was found between dietary copper intake and PID (OR = 0.23, 95% CI = 0.09-0.61, p < 0.01), as indicated by the fully adjusted model 2 (OR = 0.29, 95% CI = 0.09-0.90, p = 0.03). Simultaneously, a significant trend was found between copper intake and PID across the quintile subgroups (p for trends <0.05), suggesting a robust relationship. Furthermore, the RCS analysis demonstrated a linear correlation between PID and dietary copper intake (overall p < 0.01, non-linear p = 0.09). Conclusion: Decreased dietary copper intakes are linked to PID. However, additional research is needed to fully investigate this relationship due to the constraints of the study design.
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Neurodevelopmental disorders (NDDs) include various neurological disorders with high genetic heterogeneity, characterized by delayed or impaired cognition, communication, adaptive behavior, and psychomotor skills. These disorders result in significant morbidity for children, thus burdening families and healthcare/educational systems. However, there is a lack of early diagnosis and effective therapies. Therefore, a more connected approach is required to explore these disorders. Microglia, the primary phagocytic cells within the central nervous system, are crucial in regulating neuronal viability, influencing synaptic dynamics, and determining neurodevelopmental outcomes. Although the neurobiological basis of autism spectrum disorder (ASD) and schizophrenia (SZ) has attracted attention in recent decades, the role of microglia in ASD and SZ remains unclear and requires further discussion. In this review, the important and frequently multifaceted roles that microglia play during neurodevelopment are meticulously emphasized and potential microglial mechanisms that might be involved in conditions such as ASD and SZ are postulated. It is of utmost importance to acquire a comprehensive understanding of the complexities of the interplay between microglia and neurons to design effective, targeted therapeutic strategies to mitigate the effects of NDDs.
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Trastorno del Espectro Autista , Esquizofrenia , Niño , Humanos , Microglía/fisiología , Encéfalo , NeuronasRESUMEN
Ganoderma lucidum spore powder is a traditional Chinese medicine with a variety of health benefits. Sporoderm-removed Ganoderma lucidum spores (RGLS) can be more effectively absorbed and utilized by the body. Due to the extensive clinical application and lack of long-term (>30 days) safety evaluation of RGLS, it is necessary to evaluate its repeated dose toxicity during a longer administration period. Here, we conducted a 26-week repeated dose toxicity test of RGLS in SpragueâDawley (SD) rats. The male and female rats were orally administered RGLS at doses of 0, 0.4, 1.2, and 4.0 g/kg once daily for a period of 26 weeks. The safety profile of RGLS was assessed through in vivo observations of survival, body weight, and food consumption; hematological, biochemical, and urine analyses; immunotoxicity assays; and histopathological examinations. The results showed that no significant systemic toxicity was observed following 26 weeks of repeated RGLS administration. Our data showed a no-observed adverse effect level (NOAEL) of 4.0 g/kg, which is approximately 20 times higher than the human equivalent dose. Our results support that RGLS can be considered a safe medicinal or food product that can be added to a healthy diet.
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Ganoderma , Reishi , Humanos , Ratas , Masculino , Femenino , Animales , Esporas Fúngicas , Ratas Sprague-Dawley , Medicina Tradicional China , Nivel sin Efectos Adversos ObservadosRESUMEN
Axonal degeneration is a pathologic change common to multiple retinopathies and optic neuropathies. Various pathologic factors, such as mechanical injury, inflammation, and ischemia, can damage retinal ganglion cell (RGC) somas and axons, eventually triggering axonal degeneration and RGC death. The molecular mechanisms of somal and axonal degeneration are distinct but also overlap, and axonal degeneration can result in retrograde somal degeneration. While the mitogen-activated protein kinase pathway acts as a central node in RGC axon degeneration, several newly discovered molecules, such as sterile alpha and Toll/interleukin-1 receptor motif-containing protein 1 and nicotinamide mononucleotide adenylyltransferase 2, also play a critical role in this pathological process following different types of injury. Therefore, we summarize the types of injury that cause RGC axon degeneration and retrograde RGC death and important underlying molecular mechanisms, providing a reference for the identification of targets for protecting axons and RGCs.
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Axones , Células Ganglionares de la Retina , Células Ganglionares de la Retina/metabolismo , Células Ganglionares de la Retina/patología , Axones/metabolismo , Axones/patologíaRESUMEN
BACKGROUND: Immunotherapy, as a form of immunobiological therapy, represents a promising approach for enhancing patients' immune responses. This work aims to present innovative ideas and insights for prognostic assessment and clinical treatment of stomach adenocarcinoma (STAD) by leveraging immunobiological signatures. METHODS: We employed weighted gene co-expression network analysis (WGCNA) and unsupervised clustering analysis to identify hub genes. These hub genes were utilized to construct a prognostic risk model, and their impact on the tumor microenvironment (TME) and DNA variations was assessed using large-scale STAD patient cohorts. Additionally, we conducted transfection experiments with plasmids to investigate the influence of SPP1 on the malignancy of HGC27 and NCI-N87 cells. RESULTS: Unsupervised clustering of 12 immune-related genes (IRGs) revealed three distinct alteration patterns with unique molecular phenotypes, clinicopathological characteristics, prognosis, and TME features. Using LASSO and multivariate Cox regression analyses, we identified three hub genes (MMP12, SPP1, PLAU) from the IRGs to establish a risk signature. This IRG-related risk model significantly stratified the prognosis risk among STAD patients in the training (n = 522), testing (n = 521), and validation (n = 300) cohorts. Notably, there were discernible differences in therapy responses and TME characteristics, such as tumor purity and lymphocyte infiltration, between the risk model groups. Subsequently, a nomogram that incorporates the IRG signature and clinicopathological factors demonstrated superior sensitivity and specificity in predicting outcomes for STAD patients. Furthermore, down-regulation of SPP1, as observed after siRNA transfection, significantly inhibited the proliferation and migration abilities of HGC27 and NCI-N87 cells. CONCLUSIONS: In summary, this study highlights the critical role of immune-related signatures in STAD and offers novel insights into prognosis indicators and immunotherapeutic targets for this condition. SPP1 emerges as an independent prognostic factor for STAD and appears to regulate STAD progression by influencing the immune microenvironment.
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Adenocarcinoma , Neoplasias Gástricas , Humanos , Adenocarcinoma/genética , Neoplasias Gástricas/genética , Análisis por Conglomerados , Regulación hacia Abajo , Pronóstico , Microambiente Tumoral/genética , OsteopontinaRESUMEN
The composition of microbial microenvironment is an important factor affecting the development of tumor diseases. However, due to the limitations of current technological levels, we are still unable to fully study and elucidate the depth and breadth of the impact of microorganisms on tumors, especially whether microorganisms have an impact on cancer. Therefore, the purpose of this study is to conduct in-depth research on the role and mechanism of prostate microbiome in gastric cancer (GC) based on the related genes of bacterial lipopolysaccharide (LPS) by using bioinformatics methods. Through comparison in the Toxin Genomics Database (CTD), we can find and screen out the bacterial LPS related genes. In the study, Venn plots and lasso analysis were used to obtain differentially expressed LPS related hub genes (LRHG). Afterwards, in order to establish a prognostic risk score model and column chart in LRHG features, we used univariate and multivariate Cox regression analysis for modeling and composition. In addition, we also conducted in-depth research on the clinical role of immunotherapy with TMB, MSI, KRAS mutants, and TIDE scores. We screened 9 LRHGs in the database. We constructed a prognostic risk score and column chart based on LRHG, indicating that low risk scores have a protective effect on patients. We particularly found that low risk scores are beneficial for immunotherapy through TIDE score evaluation. Based on LPS related hub genes, we established a LRHG signature, which can help predict immunotherapy and prognosis for GC patients. Bacterial lipopolysaccharide related genes can also be biomarkers to predict progression free survival in GC patients.
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Lipopolisacáridos , Neoplasias Gástricas , Masculino , Humanos , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/genética , Neoplasias Gástricas/terapia , Pronóstico , Biomarcadores , Inmunoterapia , Microambiente Tumoral/genéticaRESUMEN
Fragile X syndrome (FXS) is a common inherited cause of intellectual disabilities and single-gene cause of autism spectrum disorder (ASD), resulting from the loss of functional fragile X messenger ribonucleoprotein (FMRP), an RNA-binding protein (RBP) encoded by the fragile X messenger ribonucleoprotein 1 (FMR1) gene. Ribonucleic acid (RNA) methylation can lead to developmental diseases, including FXS, through various mechanisms mediated by 5-hydroxymethylcytosine, 5-methylcytosine, N6-methyladenosine, etc. Emerging evidence suggests that modifications of some RNA species have been linked to FXS. However, the underlying pathological mechanism has yet to be elucidated. In this review, we reviewed the implication of RNA modification in FXS and summarized its specific characteristics for facilitating the identification of new therapeutic targets.
Asunto(s)
Trastorno del Espectro Autista , Síndrome del Cromosoma X Frágil , Humanos , Síndrome del Cromosoma X Frágil/genética , Trastorno del Espectro Autista/genética , ARN/metabolismo , Metilación , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/genética , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/metabolismoRESUMEN
The retinal pigment epithelium (RPE) is a highly specialized and polarized epithelial cell layer that plays an important role in sustaining the structural and functional integrity of photoreceptors. However, the death of RPE is a common pathological feature in various retinal diseases, especially in age-related macular degeneration (AMD) and diabetic retinopathy (DR). Mitophagy, as a programmed self-degradation of dysfunctional mitochondria, is crucial for maintaining cellular homeostasis and cell survival under stress. RPE contains a high density of mitochondria necessary for it to meet energy demands, so severe stimuli can cause mitochondrial dysfunction and the excess generation of intracellular reactive oxygen species (ROS), which can further trigger oxidative stress-involved mitophagy. In this review, we summarize the classical pathways of oxidative stress-involved mitophagy in RPE and investigate its role in the progression of retinal diseases, aiming to provide a new therapeutic strategy for treating retinal degenerative diseases. The role of mitophagy in AMD and DR. In AMD, excessive ROS production promotes mitophagy in the RPE by activating the Nrf2/p62 pathway, while in DR, ROS may suppress mitophagy by the FOXO3-PINK1/parkin signaling pathway or the TXNIP-mitochondria-lysosome-mediated mitophagy.